AU608888B2

AU608888B2 - Chemical compounds

Info

Publication number: AU608888B2
Application number: AU21553/88A
Authority: AU
Inventors: Colin Robert Gardner; Charles John Robert Hedgecock
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1987-08-28
Filing date: 1988-08-26
Publication date: 1991-04-18
Anticipated expiration: 2008-08-26
Also published as: MX173421B; NO168178C; ZA886209B; DE3884319D1; GB2209165A; HUT50474A; DK470888D0; EP0305298A3; AU2155388A; NO883522D0; GB2209165B; HU201764B; US4868176A; FI883965A7; IL87431A0; FI87074C; FI883965A0; EP0305298A2; JPS6471880A; GB8720414D0

Abstract

A compound selected from the group consisting a compound of the formula <IMAGE> I wherein R1 is selected from the group consisting of phenyl, cycloalkyl of 4 to 6 carbon atoms and <IMAGE> R4 and R5 are individually hydrogen or alkyl of 1 to 5 carbon atoms, R6 is selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, phenyl, halogen, alkoxycarbonyl of 2 to 5 carbon atoms, cyano, amido and mono- and dialkylamido of 1 to 5 alkyl carbon atoms, R2 and R3 are individually selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms and cycloalkyl of 3 to 5 carbon atoms or taken together form alkylene of 3 to 5 carbon atoms, X and Y are individually selected form the group consisting of hydrogen, halogen, -NO2, azido, -CN, -CF3 and alkyl and alkoxy of 1 to 3 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts capable of inducing an affinity for benzodiazepine receptors and a novel process and novel intermediates for their preparation.

Description

w 16m WIwI PATE,. 0FICE 1AmCmT, 1

I

F AUSTRA

L

IA

PATENTS ACT 1952 60888a10 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: e 60 o 6

S

66 0 C~ 6 60 t 0 ~c0 6 0 c6 660 C 0 CO 0 60 C 00 C $6 00 0 4 46 6 66 66 S 6 60 Complete Specification Lodged: Accepted: Lapsed: Published: Priority: Related Art: Name of Applicants: Address of Applicants: Actual Inventors: Address Address for Service: TO BE COMPLETED BY APPLICANT

ROUSSEL-UCLAF

35 Boulevard des Invalides, 75007, Paris, France.

COLIN ROBERT GARDNER and CHARLES JOHN ROBERT HEDGECOCK CALLINANS, Patent Attorneys, of 48-50 Bridge Road, Richmond 3121, Victoria, Australia.

Complete Specification for the invention entitled: "CHEMICAL COMPOUNDS" The following statement is a full description of this invention, inclu ing the best method of perfomiTng it known to us:- 7) w

U

ORIGINAL.

ta- 12X 51 991 Chemical Compounds This invention relates to imidazo benzodiazepines and acid addition salts thereof, to processes for their preparation, to pharmaceutical compositions containing them and to their use as medicaments.

According to one aspect of the invention there are provided compounds of formula I 0 S

R

2 (I) 0 R3

Y

S[wherein

R

1 represents a phenyl group, a cycloalkyl S* o 10 group containing 4 to 6 carbon atoms or a group of formula II 0 00 0 0 00 0 o o o Rr (in which R 4 represents a hydrogen atom or an alkyl group containing i to 5 carbon atoms; C 15 R 5 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms; B 0 and R 6 represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms, a phenyl group, 0$ a halogen atom, an alkoxycarbonyl group containing S f.20 2 to 5 carbon atoms, a cyano group, an amido group I tI or a mono- or dialkylamido grouo wherein the alkyl grouos contain 1 to 5 carbon atoms); IM PM ll~- lllC13 2

R

2 and R 3 which may be identical or different, each represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms or a cycloalkyl group containing 3 to 5 carbon atoms, or R 2 and

R

3 together represent an alkylene group containing 3 to 5 carbon atoms; and X and Y, which may be identical or different, each represents a hydrogen atom, a halogen atom, a nitro, azido, nitrile or trifluoromethyl group or an alkyl or alkoxy group containing 1 to 3 carbon atoms] and acii addition salts thereof.

The term "alkyl group containing 1 to 5 carbon atoms" as used herein includes straight and branchedchain alkyl groups, for example methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl or tbutyl groups.

The term "halogen atom" as used herein includes, 00 00 °0 o0 for example, fluorine, chlorine and bromine atoms.

*a0 S00 *O The term "alkoxycarbonyl group containing 2 t'o 5 carbon 06 0 S 20 atoms" as used herein includes, for example, methoxyorrrso 0 carbonyl, ethoxycarbonyl and propoxycarbonyl groups.

6 a° The term "mono- or dialkylamido group wherein the alkyl groups contain 1 to 5 carbon atoms" as used 25 herein includes, for example, monomethylamido, 0 25 dimethylamido, monoethylamido, diethylamido, mono- 04 propylamido and dipropylamido groups.

i c The acid addition salts may be those of inorganic or organic acids such as hydrochloric, hydrobromic, hydriodic, nitric, sulphuric, phosphoric, propionic, c c 30 formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic or aspartic acids, or alkanesulphonic acids such as methanesulphonic acid i 3 or arylsulphonic acids such as benzenesulphonic acid.

Preferred compounds according to the invention are compounds of formula I and acid addition salts thereof wherein

R

1 represents a cyclopropyl group; and

R

2

R

3 X and Y are as defined above.

Particularly preferred compounds according to the invention are compounds of formula I as defined above and acid addition salts thereof wherein

R

1 represents a cyclopropyl group; and

R

2 and R3' which may be identical or different, each represents a hydrogen atom or a methyl group; and X and Y, which may be identical or different, each represents a hydrogen, fluorine or bromine atom.

Of particular note is the following compound: 3-(5,6-dihydro-5-methyl-6-oxo-4H-imidazo[l,5a]j1,4]benzodiazepinyl)-cyclopropylmethanone.

The compounds according to the invention may, for 20 example, be prepared according to the following processes, which processes constitute further features of the present invention: t a I C a It a 0 0 a( a a1 A. Compounds of formula I

A

a c at c a a a ga a( a a at

R'

0 C Cr

C

a c a 4C a0 a P 0 a a 25 wherein R2' R 3 X and Y are as defined above and

R'

1 represents a cycloalkyl group containing 4-6 1 4 carbon atoms, a phenyl group or a group of formula II wherein R 4 represents a hydrogen atom and R and R 6 each represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms, may, for example, be prepared by reaction of a compound of formula

III

0 C Na x 2 3 x 9 (III) S0 3 wherein R 2

R

3 X and Y are as defined above and Ra iq a methyl or methoxy group, with a compound of formula IV M-R' (IV) "o 0 o wherein M represents an alkali metal atom 0 o o oo a lithium atom) or a group -Mg-Hal in which Hal 4" represents a chlorine, bromine or iodine atom and 1o Q 15 R' is as defined above.

.00000 0 0 The reaction of the compound of formula III with 0 OO the compound of formula IV is preferably effected under anhydrous conditions and in an organic solvent such as tetrahydrofuran.

0 00 0o 20 The compounds of formula III may conveniently be prepared by reaction of a compound of formula V Z N

(V)

x~C r .c II; 3 I- 5 t- i whArein X, Y, R 2 and R 3 are as defined above, with a compound of formula VI

(VI)

CH

3 (wherein Ra is as defined above) or an acid addition salt thereof.

The reaction between the compound of formula V and the compound of formula VI is conveniently .0 effected in dimethylformamide as solvent.

The compounds of formula V may be prepared, for example, as described in European Patent No. 109921.

B. Compound's of formula I A as defined above may, for example, also be prepared by oxidation 15 of a compound of formula VII 00 00oo o o o0o 0 0 0 0 00 0o o 0 00 000 0 9000 0 So0 000 0 0 00 000000 0 0 0 00 0 0 0 0 00 00 o oo e 0 St i> e rN 11 x 0 3

(VII)

wherein R' 1 R2' R 3 X and Y are as defined above.

The oxidation of the compound of Eormula VII is oreferably effected with manganese dioxide, nitric 20 acid, ferric chloride or chromium oxide, in the presence of pyridine, by Oppenauer oxidation or by .dehydrogenation in the presence of a copper catalyst.

1 -6 The compounds of formula VII may, for example, be prepared by reacting a compound of formula VIIf CHo

(VIII)

wherein X, Y, R 2 and R 3 are as defined above, with a compound of formula IV M

R

(IV)

wherein M and R' 1 are as defined above.

00 00 0 0 00 0 o a 000 00 0 000 0 The reaction of the compound of formula VIII with the compound of formula IV is preferably effected 10 under anhydrous conditions and in an organic solvent such as tetrahydrofuran.

0 000000 a o @G O 9 0 0 oo 0 0 0 0 00 0 00 0 04 0 0t 0 t es0 The compounds of formula VIII may, for example, be prepared as shown in published European Patent Application No. 0 027 214.

15 C. Compounds of formula I a 4 0a t 4

C~R

It R 4 s C5 R2 R 0 0 0 4 wherein R 2 R3, R4' R 5 X and Y are as defined above and R' 6 represents a hydrogen atom, a halogen atom, an alkyl group containing I to 5 carbon atoms, an alkoxycarbonyl group containing 2 to 5 carbon :I I I(L -7ratoms or a phenyl group may, for example, be prepared by reacting a compound o Eformula IX 0 R4

R

2 IIC ~(IX) X- R HC 2' 0 3 (wherein R2' R 3 R4, R 5 X and Y are as defined above) with an appropriate cyclising reagent.

it will be understood that the cyclising riagent will be a reagent serving to introduce a group CHR'6 across the vinylic double bond.

6 When a compound of formula I wherein R 4 represents oo a 10 an alkyl group containing 1 to 5 carbon atoms and 0. 0 0 0 a R represents a hydrogen atom and represents as"0 5 0 00a a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms is desired, the cyclisation is o0000 advantageously effected by means of trialkylsulphox- 00a 15 onium iodide in the presence of an organic solvent 0 4Osuch as dimethyformanide.

When a compound of formula I Swherein R 4 represents So a hydrogen atom, R rppresents an alkyl group containing

WO

0 :I to 5 carbon atoms and R1 6 represents a hydrogen 04 a 20 atom, or an alkyL group containing 1 to 5 carbon atoms is desired, the cyclisation Is advantegeously i44994 0 Seffected by means of dimethylaminoalkylhenyloxosulphonium tetrafluotoborate in the oresence of an 0 e organic solvent such as dimethylformamide.

0 4 When a compound of formula T1 wherein R 4 represents a hydrogen atom and R'j representt an alkoxycatbonyL 2- 8group or a phenyl group is desired, the cyclisation is advantageously effected by means of a dimethylsulphuranylidene acetate or benzyl dimethyl sulphonium anion in the presence of an organic solvent such as chloroform.

When a compound of formula Ig wherein R 4 represents a hydrogen atom and reoresents a halogen atom 0 is desired, the cyclisation is advantageously effected by means of a dimethylaminophenvloxosulohonium halogenomethylide in the presence of an organic solvent such as dimethylformamide.

The compounds of formula IX may, for example, be prepared by reaction of a compound of (orrnula III with a compound of formula X t 14

M-.CCH-R

5 (X) 0 0 QQ 0 0 0.o4 wherein MP R 4 and R. are as defined above.

c000 04 0 oa 00 0.0 0The reaction of the compound of formula IT with 0 the compound of foimula X is preferably effected 00 0 undet anhydrous corditions and in an organic solvent such as tetrahydrofuran.

Alternatively, comoounds of formula rX may, for .00000 example, be prepared by oxidation of a compound 9o of formula XT 0 (M C

U

wherein RV R, R, X and V are as defined above.

9 The oxidation of the compound of formula XI is preferably effected with manganese dioxide, nitric acid, ferric chloride or chromium oxide, in the presence of pyridine, or by Oppenauer oxidation or by dehydrogenation in the presence of per catalyst.

The compounds of formula XI may, for example, be prepared by reacting a compound of formula VIII CO 2

X

Y

wherein R 2

R

3 X and Y are as defined above with 0 0o a compound of formula X 0 0 00 0 R do 09 000 4 6 09 0 M- C CH R 5 (4) 00 0 wherein M, R 4 and R are as defined above.

The reaction of the compound of formula VIII with the compound of formula X is preferably effected 0 00 o0o 0 under anhydrous conditions and in an organic solvent 7 o such as tetrahydrofuran.

a 00 0eooI O. ComPounds of formula I

C

020 r r 1J Co t4 8 I

R

10 wherein RV, R 3

R

4

R

5 X and Y are as defined above and Rb and R'b, which may be identical or different, each represents a hydrogen atom or an alkyl group containing I to 5 carbon atoms may, for example, be prepared by reacting a compound of formulaIb

R

0011 wherein ~RV RV, R 4 f R 5 X and Y are as defined above, with a compound of formula XII Rb N (XU) wherein Rb and R'b are as def ined above.

The reaction of, Lhe compound of formula Iwith I 15 the compound of formula XII is preferaly~ effected i~n an anhydrous organic solvent in the, presence of carbonyldtimidazole.

The compounds of formula TD may, for example, be It prepared by saponification of a compound of formula 201B R4

'CC

S- II Swherein R 2

R

3

R

4

R

5 X and Y are as defined i above and R' 6 represents an alkoxycarbonyl group containing 2 to 5 carbon atoms.

The saponification of the compound of formula I wherein RI represents an alkoxycarbonyl group is preferably effected in an alkali metal hydroxide such as sodium hydroxide.

E. Compounds of formula I Cj4

E

a la 09 9 9 0 10 wherein R 2 R3 RV R 5 X and Y are as defined R 3 4* 100% above may, for example, be prepare' by dehydration of a compound of formula I I oo i r

BC

2 a* R Y 3* above and Rb and Rlb each represents a hydrogen atom.

The dehydration of the compound of formula T is

~C

preferably effected by means of the anhydride of a strong acid, such as trifluoroacetic acid anhydride in the presence of an organic solvent such as dichloromethane.

4* 9 000l f wherein R 2

R

4

R

5 X and Y are as defined 15 above and Rb and R'b each represents a hydrogen atom.

0The dehydration of the compound of formula Ti preferably effected by means of the anhydride of a strong acid?, such as ttifluoroacetic acid anhydride r in the presence of an organic solvent such as dlchloromethane. I 1 a I- S- 12- The compounds of formula I are basic in character and may thus, if desired, subsequently be converted into their acid addition salts.

The acid addition salts of the compounds of formula I may advantageously be prepared by reacting, in approximately stoichiometric proportions, an inorganic or organic acid with the compound of formula I.

The salts may be prepared without intermediate isolation of the corresponding base.

The compounds according to the invention possess very interesting 9harmacological properties; of particular note are the weak inverse agonist properties of some of the compounds and longer duration of action of all the compounds compared to similar reported imidazobenzodiazepines. In addition, 0o some of the compounds possess tranquillising properties.

0 0 So These properties are further illustrated in the 0

V

o oo ,0 experimental section.

0 0 000

B*

e O0; In view of their pharmacological effects, the compounds 0 o according to the invention are of use as medicaments.

Therefore the invention provides the use of compounds of formula I and pharmacologically acceptable acid addition salts thereof as medicaments.

0 *0 o0 °o Compounds according to the invention preferred 9 oa for use as medicaments are those wherein, in formula 0 2°oo 0 30 I, R 1 represents a cyclopropyl group and R 2

R

3 0o0°, :x and Y are as defined above.

0 0 Particularly preferred compounds according to the invention for use as medicaments are those wherein, in formula I, RI represents a cyclopropyl qroup; 42 and R 3 which may be identical or different, each represents a hydrogen atom or a methyl group; and X and Y, which may be identical or different, each 13 represents a hydrogen atom or a fluorine or bromine atom.

Of particular note is the following compound for use as a medicament: 3-(5,6-dihydro-5-methyl-6benzodiazepinyl)-cyclopropylmethanone and pharmaceutically acceptable acid addition salts thereof.

These medicaments can be used, 'or example, in the treatment of memory disorders, particularly in geriatrics, and in cerebral senescence disorders.

Certain compounds may also be used in the treatment of obesity and as minor tranquillisers in the treatment of certain agitated or irritated conditions, and certain forms of epilepsy.

The usual dose varies according to the compound 9 o used, patient treated and the disorder to be treated 20 and may, for example, be 0.1 mg to 200 mg of active ingredient per day, by the oral route.

0 According to a further aspect of the invention, there are provided pharmaceutical compositions containing, as active ingredient, at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof.

i As medicaments, the compounds of formula I and t 30 the. oharmaceutically acceotable acid addition salts t thereof may be incorporated into pharmaceutical compositions for the digestive or parrnteral route.

These pharmaceutical compositions may be, for example, solid or liquid and may be compositions conventionally used in human medicine, for example, plain or coated tablets, capsules including gelatin caosules, granules, suppositories, solutions e.q. for injection; these 4 14 may be prepared by conventional methods. The active ingredient(s) may be used in conjunction with excipients customarily employed in pharmaceutical compositions, such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, oreservatives.

The following intermediates useful in the preparation of the compounds of formula I are themselves new and comprise a further aspect of the invention: the compounds of formula VII 1(p o, Y (VII) 0 3 15 wherein R R R X and Y are as defined above the compounds of formula X *0 0 (5 [X3 9 15 wherein R 2

R

3 X and Y are as defined above; abv the compounds of formula XI -J Y 0 3 (XI) wherein R 2

R

3

R

4

R

5 X and Y are as defined above; t 15 the compounds of formula IX

INN

5

(IX)

Y 0 64 4.

4 6 6 66 4 4 *44 *6 o 6 4 444 6 6 e 46 4 *4 44 4 6 64 6 64 64 4 46 4 464444 6 wherein R 2

R

3 r R 4 F R 5 X and Y are as def ined above; the compounds of formula 1IT 11\ a K wherein R 2 P R 3 1 R a X and Y are as defined above; the compounds of formulaI Ll g y 0 wherein R 2 t R 3 R V P1 5 1 X and y are as defined above.

-16 The following non-limiting Examples illustrate the invention in greater detail: 9 0 4 -17- ~aaqqe 1 5, 6-dihydro-5--methvl--6--oxo-4H-irnidazo( 1,Sal [1,4 IbenzodiazeDinvi -cvcloproPv1nmthanone Step A 3- (5,6-Ditiydro-5-me tlyl-6-oxo-4 Il-imidazof I, 5aJ 1 1,4 jbenzodiaze pinyl)cyclopropylmethanol To 5 6-dihydro-3-methyl-6-oxo-411 imidazo (I 3a1( 1 4 bentodi a Cpin-3 csrboxaldehyde (1 .82g, 7,55atmol) In dry T11F (50mi) was added dropwise with stirring at ambient temperature a 0.5M solution of cyclopropyl magne,-ium bromide In T11F (22 .7mi) After headrrg under reflux for mins a furthier portion of cyclopropyl grignard was added (11.4m1) and the reaction stirred at ambient tcmperaturefor 181ira. .7he resultant suspension was poured into ice/water (1O0mi), filtered through Celite and the T11F removed under vacuum.

Extraction with chloroform (3 x 70ml), washing the extrocts with brine and drying over HgSO 4 gave a yellow Oil Flash chromatography (SiO 2 1 CHCl 3 4Z MeOll) gave 1.

4 7g of pure product (69X yield); qpt 69 0 126--128 0 C (ethyl acetate/60-80 0 C pet ether).

0 4 .J0-'i, 6 8 (br, 211); 4.19(d~d); 3.24(S,ZMeN);- 1,39(m); 0.68 and 0.50 *age,: (2xm, Ux211').

0 4 IR (KBr) 3360 br; 1640; 1630 145 L395; 1225; 1033; 942i; 760cm 1 Step B) 6 -Diydro-5-etl-Y-6-0:)-d41-imidazof I,5a 1(1,4 1benzodiazepinyl)cYciopropylmethanone 3Q cyclOpropylmethanol (L.87g, 6 6 1mmol) in methylene chloride (120MI) was stir-red withj manganiese IV oxide 7 5 g) .At lhir a further 5. 7 5 g of S HnO 2 was added and after a further 2hirs tile 'solution filtered through Celtt washing with 107. methanol in CU,1Cl.,, Th,, crude pcoduct was confentratedi.n vacuum and purified by fils ilr~matograph7 (Sib 2 f j Clici 3 Crytallization f rout hot ethyl acetate geve shlIn7 white platelets t-27& (68X yield); mpt 191,.193 0 c.

WIR, (Cool 3 7.65(d-t); 7.41(d.d); 5.28 and 4 .33(2 x br, 211),, 3.23(g, 311);, 3.18(m) .(b,2);ad10br 1-25l). 21), aid 10 t8 I R (KOr 3 10 0; 1735; 1565;' 1495; 1390; 1250; 1230; 755cm- 1

C

16 Hj 5

N

3 0R requires C, 68. 31 H, 5,37; N, 14.94.

found 68.38; H. 5.43; N, 14.94.

Examole 2: (8-Chloro-5, 6-dihydro-5-methyl-6-oxy-4Hiridazofl,S-a] [I,4lbenzodiazepin-3-yI)cyclopropylrnethanone Step A Methyl (8-chl1o ro-5,6-d ihydro-5-me thy -6-oxo-4H-imi dazo (I 5-aj( 1 benzodiazepin-3-vyl) N-methyl carbohydroxamate (Preparative Example A) I 'j To 8-chilaro-5 6 -dihiydro-5-methyl1-6-oxo-4Hi-imidazo (114]benzodiazine-3--carboxylic acid 4 .26g, 1.46mmal) dissolved in DMF 7 0m1) was added 1, ]/-carbanyldiimidazole (3 equiv, 7.12g). After stirring at 50 0 C Ear Jhirs the reaction was cooled in an ice-bath. Th e white solid was filtered off to give 3.79g of imidazolide (767 yield) which was used directly in the next step.

Thus the imidazolide (3.79g, 11.1mmol) In DMF (7Sml) was warmed, with stirring, to 60 0 C with N,O-dimethylhydroxylaoine hydrochloriv.e 3 2 5 g, 33.3mmol). After Ll'' hrs the reaction was poured into water 994/2 6*20,(3 O0ml) and extracted with ethyl acetate (3 x LOOml). Drying over 9. X gSO 4 filtering and concentrating io vacua gave a first crop of crystalli~ne product (2.89g), Further concentration gave a second crop 2 S5cng (85% yield).

StelD B (8-Chlora-5 ,6-dihydro-5-methyl-6-ox-4H-imidaza(1 (1,41 benzodiazepin-3-yl )cycl opropylme thanone To a solution of cycl1opropyl~magnesiuo bromide (1 4 .1mmo.) in dry TfIF 9 9(20m1) was added a solution of methyl(8-chloro-5,6-diydr-5-reth-yl-6oxo-4II-imldazo(1,5-a] (1, 4 ]benzodiazepln-3-yl) N-methyl carbohydroxamate in dry TUF wi-th cooling mna water bath. After stirring at ambient temperature for 80 mins the reaction was quenched with ammonium chloride solution and extracted with chloroform. The extracts were dried over MgSO4, evaporated to an oil and purified by flash chomatography in methylene chloride/echyl acetate. Crystaliisa'zion from. ethyl ncetate gave 7 0 4 mg (487 yield) of whlite crystals; rapt 230- 232 0

C.

were prepared in a similar manner to Step-A: P7eparative Example B benzodiazepin-3-yl) -N-methyl carbohydroxamate Preparative Example C (5 ,6-Dihydro-8-fluoro-5-methyl-6-oxo-4H-imidazo(1,5-a] 1,4]benzodiazepin-3-yl)-N-methyl carbohydroxamate Preparative Ex-amp).e D (8-Bromo-5,6-dihvdro-5-methyl-6-oxo-4H-imidazo( 1, 5-a] f1, 41benzodiazezpin-3-yl)-N-methyl carbohydroxamate The fol.lowing cvclopropylmethanone derivatives were prepared in a similar manner to F,'xample 2:.

Examole 3 (5,6-Dihydro-8-fluoro-5-methyl-6-oxo-4Hfl,4]benzodiazep-in-3-yl)cycloproylmnethanone 44 00 q 1 Examole 4 (8-Bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo- [1,5-a]',L.4]benzodiazepin-3-yl)cyclopropylnethanone 0 The following phenylrnethanone derivatives were prepared 4:0 in a similar manner to Example 2, but using phenylmagnesium bromide in place of cyclopropylmagnesium bromide.

Examole 5 6-Dihydro-5-methyl-6-oxo-4H-imidazot 2, 5-aj benzodiazepiin-3-yl) phenylmethanone Examole 6 6-D ihyd ro- 8- Eluoro- 5-me thyI- 6-oxo-4Himidazo(L,5-a1 fl,4]benzodiazepin-3-) phenylmethaione Examole 7 (8-Chloro-5,6-rdihydro-5-methyl-6-oxo- [1,4]benzodiazepin-3-y2.)phenylmethanone Examole 8 (B-Brqknp-5, 6-dihydro-5-methyl-6-oxo-4--midazo- (1,4benzodiazepin-3-yl~phenylmethanone Examale 9 Tabl.ets were prepared according to the formulation: Compound of Example I 20 mg Excipient for one tablet up mg (Details of excipient: lactose, otarch, talc, magnesium stearate).

-0 v 0 W e 9 9 99 9 9 9* 9 9 9, 9 9 9 9 9 999 9 9 9 99 99 9 9 9 9 9 99999 999 *99 9 9 9

I'

1 4 11914 0~ Fo~a.1. H4 N 7 1~ *1 f1zC 13903,1-30,755 5.28 4 4.33 (br,Zj); 3-223 ,1) -4.35 (br.Zl); 3.23 (8) 3.18 1.23 (a*7113; 1.09 (*,221) T32 M938 5.43 14.94 L4.-210 4.12 14.03 6.35 63.80 4.81 13.19 6.21 6.0,e6 4.4a 13.30 1l.3D 23Lk-23-2 326-V 3100.1637,I1,392 7.28-8.20 (fr.rar c4f); 121.~128~95 I5.32 4.30 Cs,3i[)- 3.20 1.25 1.11 (f.i) q Ip 153.35 3.92 11.67 22.18

C

A

6, 7 8 F 6 71 1~ 176-177 C2 85-- 160-161 3110,1635,3250,.

11.96,1356,1329~942 7-43--a-03 rratc53 -4.33 L 5.20 (r)13.93 3it); 5.203 4.430 (br,Zi); 3.92 s33 3.57 (s 3 -38 fc.31) 7.30-! 28 334.75 C19HA1.F1302 335.33 c13iIIC; 0, 56.60 4.36 17,59 5.97 564.18 4.82 17,4.6 5.96 53.82 4.53 16-73 10.59 53-61 4.57 16.69 4L751 3.99 14.77 21.07 4.51 A.60 14.67 21.30 (.5.05 4.32 12.52 5.67 4.02 11,9. 10.01 4.13 11.84 10.22 3.56 10.60 30.17 3.72 10.41 19.97 A C4 ic I4 1±.lc1 mahm- mmmlm I -22 Pharmacological Activity The compounds are agents which interact with benzodiazepine receptors in the brain, some of which may be useful for the treatment of obesity or cognitive impairment and some of which may be useful as minor tranquillizers.

Screening for benzodiazepine receptor binding CURB3) was carried out by the method described in GB 2128989.

The ability of the compounds to induce twitch in the hyoidal muscle of rats as studied according to the method of V W James and C R Gardner (Eur J Pharmacol (1985) 113 232).

Potentiation of the threshold of leptazol. induced seizures in mice by active compou.nds was measured according to (he method of Lichfield and Wilcoxon WJ Ph~rmacoi Exp Ther (1949) 96 99), Compound FR~nM Hyoida. Twitch mg/kg-- Leptazol Seizures ED 50 mg/kg L 95 2 0ip (+t-2ip 64 5 Oip Not active 3 560 00 0 4 354 6, >10,000 L 000,0 it, 3,500 12 101000 .a

Claims

2. Compounds as claimed in claim 1 wherein R represents a cyclopropyl group; and SR 2 R 3 X and Y are as defined in claim 1.
3. Compounds as claimed in claim 1 or claim 2 wherein R 1 represents a cyclopropyl group; and R 2 and R 3 which may be identical or different, each represents a hydrogen atom or a methyl group; and X and Y, which may be identical or different, each represents a hydrogen, fluorine or bromine atom.
4. 3-(5,6-Dihydro-5-methyl-6-oxo-4H-imidazo[l,5a][l,4]- benzodiazepinyl)-cyclopropylmethanone.
5. Physiologically acceptable acid addition salts of compounds of formula I as defined in claim 1.
6. Compounds as claimed in claim I as herein specifically disclosed in any one of Examples 1 to 8.
7. A process for the preparation of a compound of formula I, 6 6r 6 0 01 0 0 66 6) 6 o 6 00r 0 06r 06 6 6 66 6* 0l 6C 0 wherein R2, R 3 X and Y are as defined in claim 1 and R' 1 represents a cycloalkyl group containing 4-6 carbon atoms, a phenyl group or a group of formula II wherein R 4 represents a hydrogen atom and R5 and R 6 each represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms which comprises reaction of a compound of formula TII 'f 25 0 R N R y 0 3 (III) wherein R 2 R 3 X and Y are as defined above and Ra is a methyl or methoxy qroup, with a compound of formula IV M-R' 1 (IV) wherein M represents an alkali metal atom or a group -Mg-Hal in which Hal represents a chlorine, S1 bromine or iodine atom and R' is as defined above. 10 8. A process as claimed in claim 7 wherein the Sreaction of the compound of formula III with the compound of formula IV is effected under anhydrous conditions and in tetrahydrofuran as solvent.
9. A process as claimed in claim 7 or claim 8 wherein the compound of formula III is prepared by reaction of a compound of formula V *r 00 S Y 0 wherein X, Y, R 2 and R 3 are as defined in claim 1 with a compound of formula VI S- 26 a HN (VI) CH 3 (wherein Ra is as defined in claim 7) or an acid addition salt thereof. A orocess as claimed in claim 9 wherein the reaction between the compound of formula V and the compound of formula VI is effected in dimethyl- formamide as solvent.
11. A process for the preparation of a compound of formula I A as defined in claim 7 which comprises oxidation of a compound of formula VII R 1* the oxidation of the compound of fomula (VII) "in the esence of a copper catalyst. 4 wherein R 2 R 3 ,r X and Y are as defined in claim 7.
13. A process as claimed in claim 11 oherein St2e oxidation tof he compound of formula V isepared Seffected with manganese dioxide, nitric acid, ferric chloride or chromium oxide, in the presence of pyridine, by Oppenauer oxidation or by dehydrogenation in the presence of a copper catalyst. 13. A proc ss as claimed in claim II or claim 12 wherein the comoound of formula VII is prepared by reactinq a compound of formula VIII I I 27 CHO 2 2 x Y0 3 (VIII) wherein X, Y, R 2 and R 3 are as defined in claim 1, with a compound of formula IV M R' 1 (IV) 99 94 0 I. o 4 4 9 99 9. 9 *99 9 4 4 9. 9 9 94 9 49 O 99 44 4 *1~ .9 99 4 9' 44414 A I I wherein M and R' 1 are as defined in claim 7.
14. A process as claimed in claim 13 wherein the reaction of the compound of formula VIII with the compound of formula IV is effected under anhydrous 10 conditions and in tetrahydrofuran as solvent.
15. A process for the preparation of a compound of formula I 11f R C 4 x R2 R R R 0 3 6 wherein R 2 R 3 R 4 R 5 X and Y are as defined 15 in claim 1 and R' 6 represents a hydrogen atom, a halogen atom, an alkyl group containing I to carbon atoms, an alkoxycarbonyl group containing 2 to 5 carbon atoms or a phenyl group which comprises reacting a comp6und of formula IX 4a *i 4 I i .4 I 44 #4 4 I. 28 28 I R 2 HC (IX) 0 3 Y (wherein R 2 R 3 R 4 R 5 X and Y are as defined above) with an appropriate cyclising reagent.
16. A process as claimed in claim 15 wherein in the desired compound of formula IB, R 4 represents an alkyl group containing 1 to 5 carbon atoms, R 5 represents a hydrogen atom and R'6 reoresents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms and the cyclisation is effected by means of trialkylsulphoxonium iodide in the presence of dimethylformamide as solvent.
17. A process as claimed in claim 15 wherein in the desired compound of formula Ig, R 4 represents 15 a hydrogen atom, R 5 represents an alkyl group containing 1 to 5 carbon atoms and R' 6 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms and the cyclisation is effected by means of dimethylaminoalkylphenyloxosulphonium tetrafluoroborate 20 in the presence of dimethylformamide as solvent.
18. A process as claimed in claim 15 wherein in the desired compound of formula Ig, R 4 represents a hydrogen atom and R' 6 represents an alkoxycarbonyl group or a phenyl group and the cyclisation is effected by means of a dimethylsulphuranylidene acetate or benzyl dimethyl sulphonium anion in the presence of chloroform as solvent.
19. A process as claimed in claim 15 wherein in the desired compound of formula IB,R 4 reoresents a hydrogen atom and R' represents a halogen atom and the cyclisation is effected by means of a dimethyl- -29 aminophenyloxosulphonium halogenomethylylide in the presence of dimethylformamide as solvent. A process as claimed in any one of claims to 19 wherein the compound of formula IX is prepared by reaction of a compound of formula III as defined in claim 7 with a compound of formula X r4 M-C=CH-R 5 (X) wherein M is as defined in claim 7 and R 4 and R are as defined in claim 1.
21. A process as claimed in claim 20 wherein the reaction of the compound of formula III with the compound of formula X is effected under anhydrous I 15 conditions and in tetrahydrofuran as solvent. S22. A process as claimed in any one of claims 15 to 19 wherein the compound of formula IX is prepared by oxidation of a compound of formula I. XI CH R i (XI) y 0 3 wherein R 2 R R 4 R 5 X and Y are as defined in claim 1. S23. A'process as claimed in claim 22 wherein the oxidation of the compound of formula XI is effected with manganese dioxide, nitric acid, ferric chloride or chromium oxide, in the presence of pyridine, or by Oppenauer oxidation or by dehydrogen- ation in the presence of a copper catalyst.
24. A process as claimed in claim 22 or claim 23 wherein the compound of formula XI is prepared 1 =I i' 1 30 by reacting a compound of formula VIII i O 1j 0 (VII) wherein R 2 R 3 X and Y are as defined in claim I with a compound of formula X @4 *4 4 4 4 4 LI 4 0 0 4 44 *O 4 *II 1 R 14 M- C CH R wherein M is as defined in claim 7 and R 4 and R, are as defined in claim 1.
25. A process as claimed in claim 24 wherein the reaction of the compound of formula VIII with the compound of formula X is effected under anhydrous conditions and in tetrahydrofuran as solvent.
26. A process for the preparation of a compound of formula IC y R0 4 O R 0 R2 R' Y o 4 4* .4 I 4 II wherein R 2 R 3 R 4 R 5 X and Y are as defined in claim 1 and Rb and R'b, which may be identical or different, each represents a hydrogen atom or an alkyl qroup containing 1 to 5 carbon atoms which comprises.ceactinq a compound of formula I I 31 Y wherein RV, R 4 f R 5 X and Y are as defined above, with a compound of formula XlI ,IIRb H -N R b (×II) .0 0 a wherein Rb and R'b are as defined above.
27. A process as claimed in claim 26 wherein the reaction of the compound-of formula 1 0 with the compound of formula XII is effected in an anhydrous organic solvent in the Presence of carbonyldiimidazole.
28. A process as claimed in claim 26 or claim 27 wherein the compound of formula I D is Prepared by saponification of a compound of formula I B g0 grouo cntainin 2 to abnaos wherepifain R2 rh Ropon oV RVR n r sdforuine is effected in sodium hydroxide. A process for the preparation of a compound of formula E 4 9 32 Y 3 wherein R 2 R 3 R 4 R 5 X and Y are as defined in c'aim 1 which comprises dehydration of a compound of formula I /i 1 ab (IC) 0 0 I
31. A process as claimed in claim 30 wherein e the dehydration of the compound of formula I C is effected by means of trifbluoroacetic acid anhydride in the presence of dichloromethane as solvent.
32. A process as claimed in any one of claims 15 7 to 31 wherein a compound of formula I initially obtained is subsequedtly converted into an acid ao adaddition salt thereof and/or an acid addition salt of a compound of formula I is subsequently converted into a compound of formula 1.
33. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.
34. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 8. n -I, l i ;:ili: I -33- It @9 @09 9 9 r 9 9g 9 9 04 o19 9 9 0a 9 9) 0 @54* Compounds of formula I as defined in claim 1 and acid addition salts thereof whenever prepared by a process as defined in any one of claims 7 to 34.
36. A method of treatment of memory or cerebral senescence disorders, obesity, agitated or irritated conditions, or epilepsy, wherein is administered to the patient to be treated, an effective amount of one or more compounds as claimed in any one of claims 1 to 6.
37. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I as defined in claim 1 or a physiologically acceptable salt thereof in association with a pharmaceutical carrier and/or excipient.
38. Compositions as claimed in claim 37 wherein the active ingredient comprises a compound as defined in any one of claims 2 to 6.
39. Compositions as claimed in claim 37 or claim 38 in the form of dosage units. Compositions as claimed in claim 39 wherein each dosage unit contans from 0.1 mg to 200 mg of active ingredient.
41. Pharmaceutical compositions as claimed in claim 37 substantially as herein described.
42. Pharmaceutical compositions substantially as herein described in Example 9.
43. Compounds of formula VII as defined in claim 7.
44. Compounds of formula I1 as defined in claim 22. Compounds of formula IX as defined in claim 46, Compounds of formula III as defined in claim 7.
47. Compounds of formula I as defined in claim 26. D A T E D this 26th day oE August, 1988. ROUS SEL-UCLAF By its Patent Attorney: CALL ~NANS 94 9* 4 9 o 9* 4, '.9 99 p '99 9 *4 49 4, 4,~ 9 4, 9 0 q 9494* 4 '9 9, 4* *4, 4